DESCRIPTION: (Applicant?s Description) The major goal of this project is to determine the extent of the clinical gains that can be achieved by radiation dose escalation with proton beams. The superior dose distributions of proton beams make it possible to deliver higher tumor doses than are possible with photon beams while respecting the tolerance of critical normal tissues and organs. The proposed clinical trials will be carried out for a variety of solid tumors where conventional photon treatments have provided unsatisfactory treatment outcomes. This work will be accomplished through the mechanism of phase I/II/III clinical trials. We will assess clinical gains in terms of local control, treatment-related morbidity, distant metastasis-free survival, overall survival and quality of life. Our clinical studies in skull base and cervical spine chordomas and chondrosarcomas, paranasal sinus tumors, and choroidal melanomas, show a significant increase in local control using protons when compared to historical results with photon beams. These results were achieved with less than optimal treatment facilities at the Harvard Cyclotron Laboratory. The higher proton beam energy, isocentric gantries, and increased treatment capacity at the Northeast Proton Treatment Center make it possible to: treat disease sites throughout the body; deliver advanced proton therapy including intensity modulation; deliver treatments entirely with protons rather than giving primarily proton boost treatments; and treat patients in sufficient numbers to carry out several new clinical trials. The proposed clinical trials are based on the rationale that proton beam treatments decrease the volume of normal tissues/organs receiving high doses of radiation, thereby increasing the tolerance to radiation treatment. This makes it possible to deliver higher doses of radiation to the target/tumor volume with the expectation that higher rates of tumor control probabililty will be possible without increases in treatment morbidity. We will conduct clinical trials in lung, nasopharynx, paranasal sinus, prostate and hepatocellular cancers. In non-small-cell lung cancer we will investigate whether the reduced treatment volumes of proton beams result in decreased toxicity to chemotherapy, and hence decreased co-morbidity of radiation and concurrent chemotherapy, resulting in higher tolerated doses of both cytoxic treatments. In addition to addressing a broader spectrum of diseases in this application, we have included chemotherapy in those sites where it has become standard treatment, and have proposed quality-of-life studies to assess the total range of benefits resulting from improved dose distributions.